u-0126 and Chronic-Disease

Depression is a mental and emotional disorder that has made an opening great burden to the society. Paeoniflorin showed remarkable antidepressant-like effects in multiple animal models with depressive disorders. However, the molecule of paeoniflorin on depression is less studied. This study aims to explore the effect and the molecular mechanism of paeoniflorin on depression in a chronic restraint stress (CRS) mice model. CRS model of C57BL/6 J mice was set up. Sucrose preference test (SPT), tail suspension test (TST), open field test (OFT) and forced swimming test (FST) were used to assess depression symptoms. Immunofluorescence staining, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting were implemented to detect the expression changes of the proteins involved in extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway. Results showed that paeoniflorin treatment decreased the degree of depression in the CRS mice. Further analysis showed that the expression of ERK1/2 proteins was significantly downregulated, while paeoniflorin could elevate the expression of ERK1/2 proteins in CRS mice. Finally, it showed that inhibiting signaling ERK1/2 pathway could aggravate the depressive behavior when treatment with ERK-specific inhibitor U0126, while the condition could be partially relieved when treated with paeoniflorin. In conclusion, the present study demonstrated that paeoniflorin attenuated chronic stress-induced depression-like behavior in mice by affecting the ERK1/2 pathway. These findings provided the basis for the molecular mechanism of paeoniflorin on the effect of depression, which support paeoniflorin might act as an important drug in the treatment of depression.

Topics: Animals; Behavior, Animal; Butadienes; Cell Count; Chronic Disease; Depression; Disease Models, Animal; Gene Expression Regulation; Glucosides; Hippocampus; Male; MAP Kinase Signaling System; Mice, Inbred C57BL; Monoterpenes; Neurons; Nitriles; Stress, Psychological

Chronic stress is a potent risk factor for depression, but the mechanism by which stress causes depression is not fully understood. To investigate the molecular mechanism underlying stress-induced depression, C57BL/6 inbred mice were treated with repeated restraint to induce lasting depressive behavioral changes. Behavioral states of individual animals were evaluated using the forced swim test, which measures psychomotor withdrawals, and the U-field test, which measures sociability. From these behavioral analyses, individual mice that showed depression-like behaviors in both psychomotor withdrawal and sociability tests, and individuals that showed a resiliency to stress-induced depression in both tests were selected. Among the neuropeptides expressed in the amygdala, thyrotropin-releasing hormone (TRH) was identified as being persistently up-regulated in the basolateral amygdala (BLA) in individuals exhibiting severe depressive behaviors in the two behavior tests, but not in individuals displaying a stress resiliency. Activation of TRH receptors by local injection of TRH in the BLA in normal mice produced depressive behaviors, mimicking chronic stress effects, whereas siRNA-mediated suppression of either TRH or TRHR1 in the BLA completely blocked stress-induced depressive symptoms. The TRHR1 agonist, taltirelin, injection in the BLA increased the level of p-ERK, which mimicked the increased p-ERK level in the BLA that was induced by treatment with repeated stress. Stereotaxic injection of U0126, a potent inhibitor of the ERK pathway, within the BLA blocked stress-induced behavioral depression. These results suggest that repeated stress produces lasting depression-like behaviors via the up-regulation of TRH and TRH receptors in the BLA.

Topics: Animals; Basolateral Nuclear Complex; Butadienes; Chronic Disease; Depressive Disorder; Disease Models, Animal; Enzyme Inhibitors; Extracellular Signal-Regulated MAP Kinases; Male; Mice, Inbred C57BL; Nitriles; Psychotropic Drugs; Receptors, Thyrotropin-Releasing Hormone; Restraint, Physical; RNA, Small Interfering; Stress, Psychological; Thyrotropin-Releasing Hormone

Zymosan has previously been reported to have both pro-inflammatory and anti-inflammatory effects. Here we demonstrate that low dose zymosan prevented or reversed chronic and relapsing paralysis in EAE. In suppressing CNS autoimmune inflammation, zymosan not only regulated APC costimulator and MHC class II expression, but also promoted differentiation of regulatory T cells. Following adoptive transfer of zymosan-primed CD4(+) T cells, recipient mice were protected from EAE. In contrast, a MAPK inhibitor and a blocker of β-glucan, reversed the effects of zymosan. These results demonstrate that zymosan may be a promising beneficial agent for Multiple Sclerosis (MS).

Topics: Adoptive Transfer; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antigens, CD; Butadienes; CD4-Positive T-Lymphocytes; Cell Differentiation; Cell Line, Transformed; Chronic Disease; Coculture Techniques; Cytokines; Dose-Response Relationship, Drug; Encephalomyelitis, Autoimmune, Experimental; Enzyme Inhibitors; Female; Flow Cytometry; Gene Expression; Interferon-alpha; Lipopolysaccharides; Macrophages; Mice; Mice, Inbred Strains; Mice, Transgenic; Microglia; Myelin Proteolipid Protein; Myelin-Oligodendrocyte Glycoprotein; Nitriles; Peptide Fragments; Receptors, Antigen, T-Cell; Secondary Prevention; Severity of Illness Index; T-Lymphocytes, Regulatory; Time Factors; Tritium; Zymosan